What Is an HLA Gene?

Human leukocyte antigen (HLA) complexes help the immune system distinguish body proteins from those made by foreign invaders such as viruses and bacteria.

Essentially, there are three classes of genes in this complex:

• Class I
• Class II
• Class III

The HLA-B gene and two related genes, HLA-A and HLA-C, make up most of the major histocompatibility complex (MHC) class I genes in humans.

MHC class I genes provide instructions for producing proteins found on almost all cells' surfaces. Upon reaching the cell surface, these proteins are bound to protein fragments (peptides) that have been exported from the cell. A peptide's MHC class I molecules are displayed to the immune system. An immune system that recognizes peptides as foreign (such as viral or bacterial peptides) triggers the self-destruct response to the peptides.

Many possible variations of the HLA-B gene lead to the production of proteins that differ in at least one protein building block (amino acid). Because of this variety, each person's immune system can react to various foreign invaders. Most HLA-B gene alleles are rare, whereas others do not affect the protein function or structure. Hundreds of possible variants (alleles) of the HLA-B gene are identified by a specific number (HLA-B27, for example).

More than 60 subtypes of HLA-B27 are categorized together as closely related alleles. The subtypes are designated as HLA-B*2701 to HLA-B*2763.

Human leukocyte antigen (HLA) typing, also called tissue typing, is one of the tests you must undergo before you are placed on an organ transplant waiting list. The purpose of this test is to identify certain proteins called antigens in your blood. Antigens help your body distinguish between self and nonself by marking cells. The body can protect itself by recognizing and attacking something that does not belong to it, such as bacteria or viruses.

Furthermore, when the body detects antigens on a transplanted organ that differ from its own, it sends white blood cells to attack the organ. When your body attacks a newly formed organ, it is rejecting it. Immunosuppressants will be administered to you to prevent rejection.

Although there are many different antigens, six have been identified as having a significant role in transplantation. The antigens are A, B, and DR. Each letter consists of two antigens, which are identified by numbers. Therefore, your HLA type might be as follows:

• A2, A30
• B8, B70
• DR3, DR8

You inherit three of them from your mother (A, B, and DR) and three from your father (A, B, and DR). Children born from the same parents may inherit the same or a different set of antigens. If you have siblings, you have a 25 percent chance of inheriting the same six antigens as one of them, a 50 percent chance of inheriting three similar antigens, and a 25 percent chance of inheriting none of the same antigens. Except for identical twins and some brothers and sisters, an exact match between two individuals is extremely rare, especially if they are unrelated. The likelihood of finding an exact match with an unrelated donor is approximately 1 in 100,000. 

Although antigens are matched as closely as possible for kidney and pancreas recipients, organs are frequently transplanted to people who lack antigens. In general, these people fare well, and some may not experience rejection. In other cases, people with a six-antigen match have been rejected because unidentified antigens may be involved. There is no way to predict who will face rejection, which can occur at any time.

The cross-matching process

The cross-matching test is performed just before the transplant. A crossmatch determines whether your body has antibodies against the donor's antigens. If you have antibodies against a possible donor, you cannot safely receive a transplant from them if you are incompatible.

There are three types of tests, namely, cellular assays, immunologic and molecular tests. In most cases, human leukocyte antigen (HLA) classes are detected by polymerase chain reaction (PCR). In PCR, variable exon sequences encode the first amino terminal of HLA domains. Afterward, the database HLA sequences are used to hybridize with the amplified PCR products. Assays that detect specific HLAs, such as high-resolution melting assays, have also been developed recently.

The complement-mediated microlymphocytotoxicity procedure has long been the standard method to identify HLA class I and class II antigens. Using this technique, HLA sera are collected from multiparous alloimmunized women, and their specificities are determined by comparing them to a panel of known HLA types.

The most common testing method for HLAs is bead-based multiplexed immunoassay systems. During this test, HLA protein beads coat the surface of microspheres. Fluorescence quantification measures the amount of HLA antibody bound to each bead.

In people with HLA antibodies in their circulation, a crossmatch must be performed before transplantation. In this traditional crossmatch, blood serum from the person is mixed with lymphocytes taken from the donor. The levels of circulating HLA antibodies can be measured with single antigen beads or using multibead multiplexed immunoassay systems for "virtual" crossmatches to estimate transplant risk.

Cellular

In the immune system, HLA class I is present on the surfaces of all nucleated cells, presenting intracellular peptides to cytotoxic T-cells.

The HLA gene is essential in cellular immunity, particularly in transplant reactions. Certain antibodies, such as anti-HLA-B and anti-HLA-DQ, have complement-binding capacity.

Molecular

There can be a wide variety of HLAs, and researchers have investigated their presence and function to determine their use in disease diagnosis and treatment. The evolution of HLA polymorphisms is linked to the epidemiological composition of a particular population. Therefore, this area of research is imperative to continue exploring as technology progresses.

A study can be conducted on specific human demographics to determine if certain diseases predispose to groups of people. For example, in 2018, a study was conducted in Thailand to evaluate the efficacy of a dengue vaccine. Next-generation sequencing techniques were used to identify 201 different HLAs in the population. Through this study, researchers identified HLA alleles associated with higher frequency in the population and used that information to start applying it to disease associations in the population.

Various diseases are associated with human leukocyte antigen (HLA) without knowing the underlying pathophysiology. HLAs, however, play a role in autoimmunity. For example, the DR3-DQ2 haplotype is more prevalent in type I diabetes mellitus than in the general population. 

A similar haplotype is also associated with juvenile autoimmune thyroiditis. Haplotypes can protect against diseases, such as DRB1*14:01, which has protective effects against type I diabetes.

Human leukocyte antigen (HLA) association with disease risk

HLA types play an active role in the development of certain diseases. Here are some examples:

• HLA-B27: Ankylosing spondylitis and acute anterior uveitis
• HLA-A29: Birdshot retinopathy
• HLA-B51: Behçet's disease
• HLA-C6: Psoriasis
• HLA-DQ2,8: Celiac disease
• HLA-DR15,DQ6: Narcolepsy
• HLA-DR3,4-DQ2,8: Diabetes
• HLA-DR4: Rheumatoid arthritis 62

The HLA gene is associated with narcolepsy:

• HLA-DR2-DQ1
• HLA-DR15-DQ6
• HLA-DRB1*15:01-DQB1*06:02
• HLA-DQA1*01:02-DQB1*06:02 63

The association between HLA and celiac disease:

• HLA-A1
• HLA-A1/B8/DR3
• HLA-DR3/DQ2
• HLA-DQ2 and DQ8 64

HLA-DQ2 and HLA-DQ8 are often associated with the "Cis" heterodimer: DQA1*05 and DQB1*02, both on the DRB1*03:01 (DR17) haplotype but can also be "Trans": DQA1*05 on the DRB1*11, DRB1*12 or DRB1*13 haplotype, and DQB1*02 on the DRB1*07 haplotype.

DQA1*03 and DQB1*03:02 on a DR4 haplotype are risks associated with the DQ8 haplotype.